Acetylcholine accumulation

N-methylscopolamine (Costa et al. 1982b Schwab et al. 1983). Animals made tolerant to disulfoton were resistant to the lethal or adverse effects of cholinergic agonists, such as carbachol (Brodeur and DuBois 1964 Costa et al. 1981 Schwab and Murphy 1981) and oxotremorine (Costa et al. 1982b McPhillips 1969a), which are not hydrolyzed by acetylcholinesterase. Tissues from animals tolerant to disulfoton such as the ilea (Foley and McPhillips 1973 McPhillips 1969b McPhillips and Dar 1967) and the atria (Perrine and McPhillips 1970 Schwab et al. 1983), were resistant to the effects of carbachol and/or oxotremorine. Because the uterus and vas deferens have a relatively sparse parasympathetic innervation compared to the ileum and do not receive a steady flow of impulses via this system, these tissues were not as subsensitive to carbachol as the ileum (Foley and McPhillips 1973). Thus, acetylcholine accumulation may be a prerequisite for tolerance development. 

Although some steroids have been reported to reduce the toxic effects of some insecticides, the steroid ethylestrenol decreased the rate of recovery of depressed cholinesterase activity in disulfoton- pretreated rats (Robinson et al. 1978). The exact mechanism of this interaction was not determined. Ethylestrenol alone caused a small decrease in cholinesterase activity, and, therefore, resulted in an additive effect. Rats excreted less adrenaline and more noradrenaline when given simultaneous treatments of atropine and disulfoton compared with rats given disulfoton alone (Brzezinski 1973). The mechanism of action of disulfoton on catecholamine levels may depend on acetylcholine accumulation. In the presence of atropine, the acetylcholine effect on these receptors increases the ability of atropine to liberate catecholamines. 

They are singularly effective against cholinesterase which hydrolyzes the acetylcholine generated in myoneural junctions during the transmission of motor commands. In the absence of effective cholinesterase, acetylcholine accumulates and interferes with the coordination of muscle response. Such interference in the muscles of the vital organs produces serious symptoms and eventually death. 

C. Bronchoconstriction and secretion and muscular weaknesses occur from acetylcholine accumulation after inhibition of acetylcholinesterase. Parathion is an organophosphate insecticide that inhibits acetylcholinesterase, and it is readily available. Poisoning with compound 1080 (fluorocitrate) inhibits mitochondrial respiration and causes seizures and car-... 

Excessive muscular blockade may be caused by compounds such as the cholinesterase inhibitors. Such inhibitors, exemplified by the organophosphate insecticides such as malathion (chap. 5, Fig. 12) (see also chap. 7) and nerve gases (e.g., isopropylmethylphosphonofluor-idate), cause death by blockade of respiratory muscles as a result of excess acetylcholine accumulation. This is due to inhibition of the enzymes normally responsible for the inactivation of the acetylcholine (see chap. 7). Respiratory failure may also result from the inhibition of cellular respiration by cyanide, for example, or central effects caused by drugs such as dextropropoxyphene. 

Acetylcholine is a neurotransmitter, a key substance involved with transmission of nerve impulses in the brain, skeletal muscles, and other areas where nerve impulses occur. An essential step in the proper function of any nerve impulse is its cessation (see Figure 6.9), which requires hydrolysis of acetylcholine as shown by Reaction 6.10.1. Some xenobiotics, such as organophosphate compounds (see Chapter 18) and carbamates (see Chapter 15) inhibit acetylcholinesterase, with the result that acetylcholine accumulates and nerves are overstimulated. Adverse effects may occur in the central nervous system, in the autonomic nervous system, and at neuromuscular junctions. Convulsions, paralysis, and finally death may result. 

The pesticide family most widely used in agricultural and residential applications is the organophosphates, which affect the nervous system by reducing the ability of the enzyme acetylcholinesterase to properly regulate the concentration of the neurotransmitter acetylcholine. If acetylcholine accumulates, the nerve impulses or neurons remain active longer than usual, overstimulating the nerves and muscles and causing symptoms such as weakness or muscle paralysis and death [112]. 

Repeated or long-term exposure to low levels of nerve agents can cause neurophysiological and behavioral alterations due to down-regulation of muscarinic receptors in the hippocampus as a reaction to acetylcholine accumulation at muscarinic receptor sites based on AChE inhibition. This phenomenon is considered to be the cause of behavior performance deficits, especially disruption of cognitive functions. 

Acetylcholine is broken down by the acetylcholinesterase enzyme to choline and acetate. The time required for hydrolysis of acetylcholine is less than a millisecond. If the enzyme is depleted or inhibited, then excessive acetylcholine accumulation in the body can cause toxicity. Symptoms are salivation, lacrimation, urination, diarrhea, muscle tremor, and fasciculation. 

Following nerve agent exposure, inhibition of the tissue enzyme blocks its ability to hydrolyze the neurotransmitter acetylcholine at the cholinergic receptor sites. Thus, acetylcholine accumulates and continues to stimulate the affected organ. The clinical effects of nerve agent exposure are caused by excess acetylcholine. 

Methamidophos is a potent, direct acetylcholinesterase inhibitor that acts by interfering with the metabolism of acetylcholine. As a result, acetylcholine accumulates at neuroreceptor transmission sites. Some evidence suggests that biotransformation of methamidophos may produce a more potent anticholinesterase. 

IMS is clearly a separate clinical entity from acute cholinergic crisis and delayed neuropathy. The acute cholinergic crisis usually emerges within a few minutes to a few hours and is due to acetylcholinesterase (AChE) inhibition resulting in acetylcholine accumulation at the synapses in the nervous system and at the neuromuscular junctions. Patients acutely poisoned with OPs exhibit muscle fasciculations. 

The nerve agents are organophosphorous cholinesterase inhibitors, inhibiting butyryl-cholinesterase in the plasma and AChE in the RBCs and at cholinergic receptor sites in tissue. Acetylcholine accumulates at the nerve in receptor sites and continues to stimulate the affected organs. The chnical effect from nerve agent exposure is caused by excess acetylcholine. 

The clinical effects of nerve agents are, to a large extent, those of acetylcholine accumulation and the effects of all of the nerve agents are similar. Those differences that have been observed are presumably due to a combination of different rates of inactivation and reactivation of the enzymes, together with different rates of ageing of the inhibited enzyme and differences in absorption, distribution, metabolism and... 

When muscles in the body contract, acetylcholine is formed in the myonei ral junction, and an enzyme cholinesterase breaks down the acetylcholine t it is formed. Nerve gases act by preventing the enzyme cholinesterase fro. acting and acetylcholine accumulates in the nerve ending. In a short time tl accumulation of acetylcholine inhibits any further action of the muscles. It somewhat like the situation when too many ashes accumulate in a fire, ar finally the fire is snuffed out by the presence of ashes. The great difference that, unlike ordinary oxidation, accumulation of acetylcholine goes on rapid in terms of seconds rather than minutes. 

Symptoms (a) are due to the excess acetylcholine at muscarinic receptors. Symptoms (b) are due to excess acetylcholine at nicotinic receptors. Symptoms (c) are due to the accumulation of acetylcholine in the central nervous system. Acetylcholine accumulates because the organophosphates inhibit the enzyme acetylcholinesterase which normally removes the neurotransmitter substance. 

The phosphorylation of acetylcholinesterase is rapid while the hydrolysis of the phosphorylated enzyme is a slow process. Therefore, the enzyme is unable to function on prolonged blocking of the esteratic site. Acetylcholine accumulates which finally results in endogenic acetylcholine poisoning. 

Physostigmine competitively blocks acetylcholine hydrolysis by cholinesterase, resulting in acetylcholine accumulation at cholinergic synapses that antagonizes the muscarinic effects of overdose with antidepressants and anticholinergics. With ophthalmic use, miosis and cihary-muscle contraction increases aqueous humor outflow and decreases lOP. 

Fig. 8.17 A. Acetylcholinesterase normally catalyzes inactivation of the neurotransmitter acetylcholine in a hydrolysis reaction. The active site serine forms a covalent intermediate with a portion of the substrate during the course of the reaction. B. Diisopropyl phosphofluoridate (DFP), the ancestor of current organophosphorus nerve gases and pesticides, inactivates acetylchohnesterase by forming a covalent complex with the active site serine that cannot be hydrolysed by water. The result is that the enzyme cannot carry out its normal reaction, and acetylcholine accumulates.

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